Simeprevir and sofosbuvir with or without ribavirin to treat recurrent genotype 1 hepatitis C virus infection after orthotopic liver transplantation.

Although combination simeprevir (SIM) plus sofosbuvir (SOF) is an approved regimen for genotype 1 chronic hepatitis C virus (HCV), data regarding its safety and efficacy in liver transplant recipients remain limited. A multicenter retrospective study was performed to determine the efficacy and tolerability of a 12-week regimen of SIM/SOF with or without ribavirin (RBV) in 56 consecutive liver transplant recipients in 2014; 79% of patients had genotype 1a, 14% had cirrhosis, and 73% were treatment experienced. Sustained virological response at 12 weeks (SVR12) was 88% by intention to treat analysis (95% confidence interval, 84%-90%). Four patients relapsed, but no on-treatment virological failures occurred. The Q80K polymorphism did not impact SVR12, but there was a trend toward decreased sustained virological response with advanced fibrosis (P = 0.18). HCV RNA was detectable at treatment week 4 in 21% of patients, and those who had detectable levels were less likely to achieve SVR12 (58% versus 95%; P = 0.003). Five patients had baseline Child-Pugh class B cirrhosis, and 2 of them died (1 following early discontinuation of therapy). An additional discontinuation resulted from a severe photosensitivity reaction in a patient on concomitant cyclosporine. Seven patients receiving RBV developed progressive anemia requiring intervention. Immunosuppression dose modifications were minimal. SIM/SOF for 12 weeks was effective and well tolerated by compensated liver transplant recipients especially when administered without concomitant RBV or cyclosporine. SIM/SOF appears to have a niche as the only 12-week RBV-free treatment regimen currently recommended by guidelines for compensated transplant recipients. However, 12 weeks may not be the optimal duration of therapy for those with detectable virus at week 4 or possibly for those with cirrhosis. These data require confirmation by prospective randomized clinical trials. Liver Transplantation 22 635-643 2016 AASLD.

Rapid early HDV RNA decline in the peripheral blood but prolonged intrahepatic hepatitis delta antigen persistence after liver transplantation.

BACKGROUND & AIMS: Chronic HDV infection is an inflammatory liver disease and liver transplantation (LTX) remains the only curative treatment option for most patients. The hepatitis D virus (HDV) uses HBsAg as its surface protein, however, it is controversial to what extend HDV may be detected independently of HBsAg in blood and liver after LTX. The aims of this study were to investigate kinetics of HDV RNA and HBsAg early after LTX, to apply the data to a mathematical model and to study long-term persistence of HDV after LTX. METHODS: We retrospectively analyzed 26 patients with chronic hepatitis delta who underwent LTX between 1994 and 2009. Blood samples were obtained every 1-3 days during the first 14 days after LTX. Data were applied to a mathematical model to study viral kinetics. Available liver biopsy samples were stained for HBV and HDV viral antigens and tested for HBV DNA/cccDNA. RESULTS: HBsAg and HDV RNA became negative after a median of 5 days (range 1-13) and 4 days (range 1-10), respectively. Early HDV RNA and HBsAg decline paralleled almost exactly in all patients; however the mathematical model showed a high variability of virion death. HDAg stained positive in transplanted livers in six patients in the absence of liver HBV DNA/cccDNA, serum-HBsAg, and HDV RNA for up to 19 months after LTX. CONCLUSIONS: HDV RNA and HBsAg decline follow almost identical kinetic patterns within the first days after LTX. Nevertheless, intrahepatic latency of HDAg has to be considered when exploring novel concepts to withdraw HBIG.

High rate of unperceived hearing loss in patients after liver transplantation.

AIM: We recently published the high frequency of perceived hearing impairment in adults after orthotopic liver transplantation (OLT). To obtain objective data in addition to the questionnaires, audiometric data of 70 patients' post-OLT were analyzed. METHODS: Hearing tests were obtained from 70 patients who were in follow-up 6.5 ± 4.3 yr after OLT. Thirty-eight of these patients (53%) reported the development of a hearing problem post-OLT, while 14 patients already noticed hearing loss prior to OLT (21%). Eighteen patients did not report any hearing problems (26%). RESULTS: Audiometry was within the normal range only in five patients (7%). Signs of mild or moderate hearing loss were found in 12 (17%) and 28 patients (40%), respectively. In 25 patients, audiometry revealed even severe hearing loss (36%). In 86% of patients, hearing loss was bilateral affecting all frequency areas in 63%. Of the 18 patients without subjective hearing impairment, moderate or severe hearing loss was found in 50% of audiometries. Mean maximal hearing loss was -62 ± 30 dB with worse results in patients reporting hearing problems (p < 0.03). CONCLUSIONS: We confirmed the high incidence of reported hearing loss in adults post-OLT by objective audiometric data. Pathological hearing tests were even found in many patients without perception of hearing impairment.

Changes in plasma amino acids during extracorporeal liver support by fractionated plasma separation and adsorption.

In patients with liver failure, amino acid dysbalance is common and associated with hepatic encephalopathy. Prometheus is a newly designed extracorporeal liver support system based upon fractionated plasma separation and adsorption (FPSA). We evaluated the influence of FPSA on plasma amino acid patterns in patients with liver failure and hepatic encephalopathy. We studied nine patients with acute-on-chronic liver failure, hepatic encephalopathy, and concomitant renal failure. A single session of FPSA therapy for 5 +/- 1 h was performed in all patients. Twenty-six different plasma amino acids were measured by high-performance liquid chromatography before and after FPSA treatment. Total amino acids as well as Fischer index were calculated. Additionally, a variety of clinical and biochemical parameters were assessed. Before FPSA was started, plasma levels of most amino acids were elevated. Plasma ammonia levels correlated with glutamine levels (P < 0.04). During FPSA, plasma levels of nearly all amino acids significantly decreased except for branched-chain amino acids. The Fischer index improved without reaching statistical significance. FPSA therapy tends to normalize plasma amino acids in patients with combined liver and renal failure. This may contribute to positive pathophysiologic effects, especially on hepatic encephalopathy. However, the clinical significance of these findings needs to be further evaluated.

A decline in hepatitis B virus surface antigen (hbsag) predicts clearance, but does not correlate with quantitative hbeag or HBV DNA levels.

BACKGROUND: The elimination of hepatitis B virus surface antigen (HBsAg) is the final goal of hepatitis B treatment, but is rarely achieved. As quantitative assays for HBsAg recently became available, we have investigated whether quantitative HBsAg measurements can substitute for hepatitis B virus (HBV) DNA quantification in treatment monitoring. METHODS: Within this study, 23 liver transplant patients and 18 heart transplant recipients were retrospectively analysed. Patients had been treated with famciclovir and/or lamivudine, in addition some had also received adefovir in cases of lamivudine resistance. Quantitative HBsAg and hepatitis B virus e antigen (HBeAg) levels were determined with the Architect assay. HBV DNA levels were determined with different assays available at given time points. RESULTS: We did not find a significant correlation between either HBsAg or HBeAg and HBV DNA levels - both in treated and untreated patients. More importantly, there was no significant concordance between an increase or decrease of HBsAg or HBeAg with HBV DNA. However, the curve and decline of quantitative HBsAg enabled prediction of eventual viral clearance. Eight patients showed a 2 log10 drop of HBsAg levels and eight patients demonstrated a reduction of HBsAg levels below 100 IU/ml; five patients fulfilled both criteria. Three of those five cleared HBsAg and became positive for antibodies against HBsAg. CONCLUSIONS: Quantitative HBsAg and HBeAg cannot substitute for HBV DNA quantification during the assessment of antiviral therapy; however, the decline of HBsAg does predict eventual HBsAg clearance. A 2 log10 drop to below 100 IU/ml is associated with a high likelihood of HBsAg clearance.

Antibody to hepatitis B surface antigen trough levels and half-lives do not differ after intravenous and intramuscular hepatitis B immunoglobulin administration after liver transplantation.

Hepatitis B immunoglobulin (HBIG) administration remains an essential component of standard reinfection prophylaxis after liver transplantation for hepatitis B virus-related liver disease. Previous studies have suggested that intramuscular (IM) HBIG administration compared to intravenous (IV) HBIG administration may be cost-effective and dose-saving. To compare antibody against hepatitis B surface antigen (anti-HBs) kinetics after IV HBIG administration versus IM HBIG administration, 24 patients received 2000 IU of HBIG every 6 weeks over a study period of 48 weeks in a crossover design. HBIG was started intravenously in 12 patients (group A) and intramuscularly in 12 patients (group B). After 4 doses, at week 24 HBIG administration was switched from IM to IV and vice versa. Anti-HBs kinetics of 22 patients were evaluated. Mean anti-HBs levels measured 2, 4, and 6 weeks after each HBIG administration did not differ significantly (480 +/- 166, 319 +/- 126, and 221 +/- 106 IU/L after IV administration versus 457 +/- 166, 310 +/- 147, and 218 +/- 112 IU/L after IM administration). Half-lives of anti-HBs decline (IV, 25.5 +/- 6.0 days, versus IM, 24.7 +/- 6.2 days) and area under the curve values from week 2 to 6 (IV, 9.4 +/- 3.6 IU*day/mL, versus IM, 9.0 +/- 3.9 IU*day/mL) also showed no significant difference. Variation of anti-HBs levels after IV HBIG administration versus IM HBIG administration was neither significantly different within patients (intraindividual variance) nor between patients (interindividual variance). However, intraindividual variance was lower than interindividual variance after IV (P < 0.05) and IM (P < 0.05) HBIG administration at every time point (2, 4, and 6 weeks). In conclusion, IV HBIG administration and IM HBIG administration are equally effective with respect to the crucial pharmacokinetic parameters. That is, IM HBIG is not dose-saving; however, it may be cost-effective if the price per unit is lower. Individualized dosing intervals should be further evaluated as a cost-effective alternative to fixed dosing schemes.

Ki67, E-cadherin, and p53 as prognostic indicators of long-term outcome after liver transplantation for metastatic neuroendocrine tumors.

BACKGROUND: Patients suffering from hepatic metastases of neuroendocrine tumors (NET) are potential candidates for orthotopic liver transplantation. Because recurrence rates are high and outcome is variable, prognostic indicators are required. The aim of our study was to identify predictors of long-term survival with a focus on the impact of tumor biology. METHODS: We retrospectively analyzed 19 patients who received an orthotopic liver graft for metastatic NET at the Medizinische Hochschule Hannover. Expression of Ki67, E-cadherin, and p53 was studied immunohistochemically in metastases of neuroendocrine tumors of the explanted livers. RESULTS: Patients were followed up to 146 months after liver transplantation. Six patients died during follow-up. The resulting 1-, 5-, and 10-year survival rates are 89%, 80%, and 50%, respectively. All deaths during long-term follow-up were tumor-associated. Recurrence was diagnosed in 12 patients between 2 weeks and 48 months after liver transplantation. Three patients are without tumor recurrence more than 8 years after liver transplantation. Survival in the 5 patients with low Ki67 and regular E-cadherin staining was significantly better than in the 12 patients with high Ki67 or aberrant E-cadherin expression (7-year survival 100% vs. 0%, respectively, log rank P=0.007). p53 expression did not significantly improve prognostic accuracy. CONCLUSIONS: We conclude that analysis of Ki67 and E-cadherin expression may improve the identification of patients with a favorable prognosis after liver transplantation for metastatic neuroendocrine tumors.

Longer survival of liver transplant recipients with hepatitis virus coinfections.

Hepatitis virus coinfections [HBV plus HCV coinfection (HBV/HCV) or HBV plus HDV coinfection (HBV/HDV)] may progress more rapidly to cirrhosis than hepatitis B or C monoinfections in immunocompetent patients. Only limited information is available on the outcome of coinfected patients after liver transplantation. We studied survival rates of 204 patients with viral hepatitis transplanted at our center between 1972 and 1997. HBV/HDV and HBV/HCV coinfections were present in 23 and nine individuals, respectively, while 97 patients had monoinfection by HCV and 75 had HBV monoinfection. Survival of coinfected patients was significantly longer than that of monoinfected patients (14.4 +/- 0.9 vs. 8.5 +/- 0.6 yr; p = 0.0003). The same was true for graft survival (p = 0.0002). In Cox's regression, viral coinfection (p = 0.0001), absence of hepatocellular carcinoma (HCC) (p = 0.00001) and no retransplantation (p = 0.02) were independently associated with patient survival. After exclusion of patients with HCC (n = 62), survival of coinfected patients was still significantly longer than that of monoinfected individuals (p = 0.002). The improved outcome was similar for both HBV/HDV and HBV/HCV coinfections. In contrast to immunocompetent patients, individuals with multiple hepatitis virus infections had an improved outcome after liver transplantation. Thus, viral coinfections may be associated with ameliorated courses of diseases under certain conditions.

HBsAg level at time of liver transplantation determines HBsAg decrease and anti-HBs increase and affects HBV DNA decrease during early immunoglobulin administration.

BACKGROUND/AIMS: Administration of hepatitis B immunoglobulin (HBIG) initially after liver transplantation of hepatitis B patients is considered important to prevent reinfection reliably. However, dosing schedules differ considerably between centers. We measured HBsAg, anti-HBs and HBV DNA kinetics to create a rational basis for dosing schemes. METHODS: Thirteen patients (group A) received 10,000 IU HBIG in the anhepatic phase followed by 10,000 IU daily until HBsAg became negative, whereas five patients (group B) received 20,000 IU followed by 5000 IU every 30 min. RESULTS: HBsAg levels at time of transplantation ranged from 0.12 to 12,990 IU/ml. Correlations between initial HBsAg and HBIG required to decrease HBsAg below 1 IU/ml were high in groups A and B (r=0.97, p<0.001; r=1.00, p<0.001), as were correlations between initial HBsAg and HBIG required to raise anti-HBs above 1000 IU/l (r=0.94, p<0.001; r=1.00, p<0.001). In 11 HBV DNA-positive patients, DNA levels became negative in seven, and dropped by 2.5 log10 (mean) in the other four patients during immunoglobulin administration. CONCLUSIONS: In conclusion, required HBIG doses to decrease HBsAg and raise anti-HBs are determined by HBsAg levels at time of transplantation, not by HBV DNA levels. Shortened HBIG dosing intervals accelerate HBsAg decrease and anti-HBs increase. HBV DNA decreases rapidly during HBIG administration in most patients.

Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation.

Hepatitis B vaccination after liver transplantation for hepatitis B-related liver disease has been investigated as an alternative strategy to reinfection prophylaxis with hepatitis B immunoglobulin (HBIG) with conflicting results. In most studies, HBIG treatment was discontinued before vaccination. An outstanding good response was achieved with vaccination under continuous HBIG administration using hepatitis B surface antigen (HBsAg)-based vaccine containing special adjuvants. Both, adjuvants and continuous HBIG administration have been discussed as crucial factors for good response. Twenty-four patients were vaccinated with conventional double dose recombinant vaccine containing 40 microg HBsAg up to 12 times at weeks 0, 2, 4 (cycle 1), 12, 14, 16 (cycle 2), 24, 26, 28 (cycle 3), and 36, 38, 40 (cycle 4). All patients received 2,000 IU HBIG every 6 weeks (4 times intravenously and 4 times intramuscularly). A significant response was defined as reconfirmed increase of anti-HBs-antigen (anti-HBs) unexplained by HBIG administration or lack of anti-HBs decrease below 100 IU/L after discontinuation of HBIG treatment after week 48. Only 2 of 24 patients (8.3%) responded significantly. Anti-HBs started to increase after the seventh vaccination (cycle 3, during intramuscular HBIG administration) in 1 patient and after 12th vaccination (cycle 4, during intravenous HBIG administration) in the other. Maximum anti-HBs levels were >1,000 IU/L in both patients and decreased significantly slower as compared to passive prophylaxis during follow-up. In conclusion, the conventional HBsAg vaccine failed to induce a significant humoral immune response in most patients despite continued HBIG treatment. Further studies should address the question, of whether the use of potent adjuvant systems results in higher response rates.

Treatment of severe refractory pruritus with fractionated plasma separation and adsorption (Prometheus).

OBJECTIVE: Severe pruritus is a serious complication of cholestatic liver disease. Prometheus is a recently introduced extracorporeal liver support system with direct toxin adsorption of the patient's albumin fraction (FPSA; fractionated plasma separation and adsorption). Here we report on the effect of Prometheus therapy in patients with intractable cholestatic pruritus. MATERIAL AND METHODS: Seven patients with different liver diseases and severe pruritus refractory to all medical treatment efforts for more than 4 weeks were treated with Prometheus (3-5 times, 18+/-3 h total). Pruritus intensity was assessed using the visual analogue scale (VAS; from 0 = no pruritus to 10 = unbearable pruritus), and VAS, serum bile acids and total bilirubin were evaluated directly before and after Prometheus treatment, as well as 4 weeks later. RESULTS: After Prometheus therapy, VAS values had dropped significantly from 9+/-1 to 3+/-3 (p<0.001). Likewise, serum bile acids decreased (from 248+/-192 to 101+/-85 micromol/l; p<0.03). All patients, with the exception of one with no initial bile acid elevation, reported a pronounced improvement in pruritus with Prometheus therapy, although in two anicteric patients the amelioration lasted only a few days. In the other four patients a distinct benefit was still observed 4 weeks after the treatment. CONCLUSIONS: Prometheus therapy significantly improved refractory pruritus in all patients with elevated bile acid levels, but in some patients the clinical benefit was of short duration. The clinical findings suggest that we have to better characterize those patients who might derive a long-lasting benefit from this invasive and expensive treatment.

A new side effect of immunosuppression: high incidence of hearing impairment after liver transplantation.

Little is known about hearing impairment in patients after organ transplantation. We conducted a single-center study to evaluate hearing impairment in patients after orthotopic liver transplantation (OLT). A questionnaire was sent to 695 adult patients after OLT to assess characteristics and course of auditory impairment. Risk factors such as ototoxic drugs were taken into consideration. Clinical follow-up, including immunosuppressive therapy, was analyzed in detail. The questionnaire was completed by 521 patients (75%). Hearing impairment was reported by 184 patients (35%). A total of 43 patients (8%) suffered from hearing abnormalities prior to OLT. The remaining 141 patients (27%) developed hearing impairment after transplantation. Main problems were hearing loss (52%), tinnitus (38%), and otalgia (30%). There was no association of post-OLT hearing disorders with age or known risk factors. In 43% of patients, onset of hearing impairment was within 2 yr post-OLT. Hearing loss was positively associated with tacrolimus immunosuppression in univariate (P < 0.05) and multivariate analysis (P < 0.02). Patients using a hearing aid received tacrolimus more frequently than cyclosporine (P < 0.05). In conclusion, subjective hearing impairment is frequent in patients after OLT and contributes to post-OLT morbidity. Calcineurin inhibitor-related neurotoxicity appears as a possible mechanism. Further prospective investigations with objective hearing tests are necessary to confirm these results and to evaluate the role of immunosuppression.

Hepatitis B virus immunization with an adjuvant containing vaccine after liver transplantation for hepatitis B-related disease: failure of humoral and cellular immune response.

Long-term hepatitis B reinfection prophylaxis after liver transplantation with hepatitis B immunoglobulin (HBIG) and nucleoside analogues is expensive and inconvenient. Studies evaluating humoral immune responses to hepatitis B virus (HBV) vaccines showed conflicting results. Best results were achieved under continuous HBIG administration with an adjuvant-containing HBsAg vaccine. In the present study, 8 patients who had been HBsAg positive and HBV DNA negative prior to liver transplantation were immunized with HBsAg-vaccine containing the adjuvant 3-deacylated monophosphoryl-lipid-A. Vaccination was started after discontinuation of HBIG. Six vaccinations were administered at weeks 0, 2, 4, 12, 16 and 24. Humoral (anti-HBs titres) and cellular (enzyme-linked immunospot assay and fluorescence-activated cell sorting analysis) immune responses were studied. Only one of eight patients responded with a humoral immune response (maximum anti-HBs titre 561 U/l). In this patient, decrease of anti-HBs titre before vaccination was significantly slower than in the other seven patients and anti-HBs did not become negative before first vaccination. A T-cell response to HBsAg could not be detected in any of the patients. The responder was the only patient who showed a T-cell response to HBcAg. In conclusion, the adjuvant-containing vaccine did not induce a humoral or a detectable cellular immune response in most patients. Patient-related preconditions and concomitant HBIG administration should be further investigated as possible predictors for response.

Successful treatment of fibrosing cholestatic hepatitis using adefovir dipivoxil in a patient with cirrhosis and renal insufficiency.

Fibrosing cholestatic hepatitis is a deleterious manifestation of hepatitis B virus infection in immunocompromised patients. Without treatment, this condition is usually fatal within weeks of onset. Liver retransplantation has not been successfully performed to date, and treatment intervention was generally unsuccessful before the advent of adefovir dipivoxil. However, concerns have been expressed about the use of this agent in patients who are renally compromised. A 40-year-old liver transplant recipient with hepatitis B virus reinfection, resistance to lamivudine, and fibrosing cholestatic hepatitis complicated by terminal renal impairment and spontaneous bacterial peritonitis was treated with adefovir dipivoxil 10 mg after every dialysis. Since initiating treatment with adefovir dipivoxil 10 mg, a dramatic virologic and clinical improvement was observed in this patient. The patient returned to work full-time within 6 months of starting adefovir dipivoxil without the need for liver retransplantation. Serum HBV DNA (Amplicor HBV; Roche Diagnostics, Basle, Switzerland) decreased by 6 log(10) copies/mL and became negative (< 400 copies/mL) within 8 weeks of treatment and remains negative at the last available assessment. The patient continues to require renal dialysis, but is generally well. Creatinine clearance improved from 8 mL/min to 16 mL/min during the course of treatment. No adverse events related to adefovir dipivoxil were observed. Adefovir dipivoxil resulted in significant clinical improvement in this patient with hepatitis B virus-induced fibrosing cholestatic hepatitis, despite the presence of renal impairment and lamivudine resistance.